Unraveling the inhibitory potential of fatty acids from Cola lepidota seed against monoclonal antibody Fab fragment (9F8) (3VG0) leptin antagonism and restoration of ‘satiety’ in obesity condition: insight from quantum chemical analysis, pharmacokinetics, and molecular docking

Abstract

Abstract Obesity represents a significant global health issue that continues to escalate in prevalence. Interestingly, there is a less explored connection between obesity and compromised leptin function. Prior studies have highlighted the limited availability of drugs to address this issue hence, the relentless struggle against obesity persists and the need to develop new therapeutic strategies becomes necessary. In the present study, fatty acids from the seed of Cola lepidota were utilized to prevent antibody Fab fragment (9F8) (3VG0), an antagonist of leptin from binding to the leptin pocket of the human obesity receptor (ObR) thereby restoring ‘satiety’. This study is the first to investigate the effect of plant derived fatty acids from C. lepidota seed for the purpose of reversing leptin resistance in obesity condition. Our research employed experimental GCMS extraction technique and theoretical FT-IR and UV–vis analysis and compared result with those reported in literature. All computational methodologies were carried out within the framework of density functional theory (DFT) at the B3LYP/6-311++G(d,p) level of theory while molecular docking and pharmacokinetics studies were employed to investigate the biological activities and druglikeness of the compounds. Result shows that linoleic acid (LA), methylhexadecanoate (HXD), ocatadecanoic acid methyl ester (ODA) and Bis(2-ethylhexyl) phthalate (BISP) recorded energy gaps of 2.8216 eV, 7.4230 eV, 7.4244 eV, and 5.5849 eV respectively, suggesting that LA is the most reactive while BISP is the most stable as they recorded lowest and highest energy gaps respectively. The dipole moment (μ) result shows that LA recorded the highest dipole moment at 6.1119 Debye (D) indicating that it has the highest polarizability capacity. The order of polarizability is LA > BISP > HXD > ODA. The visualized electron localization function result shows that the red regions are electron rich, followed by yellow region then green and finally blue region. Electron density was distributed within the O and H atoms of the molecules indicating strong electronegativity nature of oxygen and hydrogen atoms of the compounds. LA, ODA and HXD absorbed light at the vacuum level UV region while BISP absorbed light at the UV visible region. The compounds exhibited C–H and C–O stretching vibrations except for ODA that lacks the C–O functional group. The compounds exhibited biological activities with the target receptor protein (leptin antagonist) with bis(-2ethylhexyl) phthalate (BISP) having a docking score of −4.4 kcal/mol and containing the highest number of favorable hydrogen bond interactions with LYS41, PRO42, GLN44, GLY43 residues along the polypeptide L chain and PRO173 along the polypeptide H chain of the receptor. These interactions predominantly induced conformational changes in the amino acid sequence of the protein, thereby disrupting its three-dimensional structure and mitigating the antagonistic effects at the leptin binding domain (LBD) of the human obesity receptor (ObR), thus, effectively reversing leptin resistance in obese condition. Importantly, the pharmacokinetics revealed favorable drug-like properties with no toxicity effects with respect to hepatotoxicity, immunotoxicity, cytotoxicity, mutagenicity, carcinogenicity and did not also penetrate the blood-brain barrier (BBB) or exhibit clearance delays. The therapeutic strategy presented in this study is highly thoughtful and capable of recording huge success in obesity management, thereby reducing the burden of obesity on other chronic diseases. Therefore, these compounds have positioned themselves as promising agents in leptin resistance reversal and obesity management, warranting significant interest as potential drug candidates.